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Indian Journal of Pharmacology
Medknow Publications on behalf of Indian Pharmacological Society
ISSN: 0253-7613 EISSN: 1998-3751
Vol. 36, Num. 4, 2004, pp. 256-256
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Indian Journal of Pharmacology, Vol. 36, No. 4, August, 2004, pp. 256
Correspondence
Selective cyclooxygenase-2 inhibitors in inflammatory bowel disease
Kulkarni SK, Singh VP
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh -160 014
Correspondence Address:Pharmacology Division, University Institute
of Pharmaceutical Sciences, Panjab University, Chandigarh -160 014 skpu@yahoo.com
Code Number: ph04087
Sir,
The gastric (ulcer-producing) adverse relationship of conventional non-steroidal
antiinflammatory drugs (NSAIDs) is now well recognized.[1] NSAIDs
non-specifically inhibit the cyclooxygenase enzymes (COX-1 and COX-2)
leading to loss of gastric mucosal integrity and at the same time producing
the desired antiinflammatory effect.[2] It
has been proposed that selective COX-2 inhibitors (coxibs) are non-toxic
to the gastrointestinal tract by sparing COX-1 while retaining the potential
antiinflammatory effect.[3] It
was on this background that the NSAIDs, particularly the selective COX-2
inhibitors were indicated in inflammatory bowel disease (IBD). However,
recent reports indicate conflicting clinical observations (exacerbation
or amelioration) of IBD with the use of coxibs, the new COX-2 inhibitors.[4],[5],[6],[7]
Long-term administration of COX-2 inhibitors to knockout mice (genetically
COX-2 deficient) led to development of significant intestinal pathology
suggesting that COX-2 products are involved in the maintenance of bowel
integrity.[8] The mechanism(s)
underlying the intestinal damage and aggravation by coxibs have been poorly
explored. COX-2 expression was reported to be increased in the colonic
mucosa in both experimental colitis[9] and
colitis of IBD,[10] suggesting
its protective role in healing. It could thus be speculated that the suppression
of elevated COX-2 levels by coxibs leads to further deterioration of active
IBD. First-degree relatives of patients with Crohn′s disease experienced
increase in small bowel permeability with use of coxibs.[11] A
genetic component may also be involved in IBD.
However, it remains uncertain whether the coxibs-mediated increase
is linked to the depletion of cytoprotective prostaglandins derived via
this isoform[12] or
whether it is due to the mucosal exposure of luminal antigens that trigger
local inflammatory reaction.[4] Recently,
a new role of COX-2 in the maintenance of oral tolerance has been suggested.
The tolerance of the intestinal immune system is assumed to be disrupted
in IBD, thus causing enhanced reactivity of mucosal flora.[13],[14]
Further, the induction of COX-2 enzyme in apical and lamina propria mononuclear
cells of the intestine in IBD patients suggests a function for COX-2
in repairing damaged tissue.[10] Moreover,
coxibs do not provoke injury on previously normal intestine.[5] Thus,
it is theoretically possible that active IBD might be even more specifically
worsened by coxibs.
Though the clinical evidence is still preliminary these observations
raise concern regarding the use of coxibs in preexisting IBD. However,
the chemopreventive
activity of coxibs against colorectal carcinomas arising from ulcerative
colitis[15] might further
justify the potential application of selective COX-2 inhibitors in IBD.
Thus, at the moment, the use of coxibs in patients with inflammatory
bowel disease should be viewed with the same caution as with the use
of conventional
NSAIDs.
REFERENCES
1. | Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97-120. Back to cited text no. 1 [PUBMED] [FULLTEXT] |
2. | Crybe B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal antiinflammatory drugs. Am J Med 1998;104:413-21. Back to cited text no. 2 |
3. | Masferrer Jl, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, et al. Selective inhibition of Schachna. Med J Aust 1999;171:175-6. Back to cited text no. 3 |
4. | Bonner F. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001; 91:1306-8. Back to cited text no. 4 |
5. | Gornet JM, Hassani Z, Modiglian R, Lemann M. Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on rofecoxib. Am J Gastroenterol 2002;97:3209-10. Back to cited text no. 5 [PUBMED] [FULLTEXT] |
6. | Reinisch W, Miehsler W, Dejaco C, Harrer M, Waldhoer T, Lichenberger C, et al. An open-label trial of the selective cyclooxygenase-2 inhibitor, rofecoxib, in inflammatory bowel disease-associated peripheral arthritis and arthralgia. Aliment Pharmacol Ther 2003; 17: 1371-80. Back to cited text no. 6 |
7. | Mahadevan U, Loftus, EV Jr, Tremaine WJ, Sandborn WJ. Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Am J Gastroenterol 2002; 97:910-4. Back to cited text no. 7 |
8. | Sigthorsson G, Simpson RJ, Walley M, Anthony A, Foster R, Hotz-Behoftsitz C, et al. COX-1 and COX-2, intestinal integrity, and pathogenesis of nonsteroidal antiinflammatory drug enteropathy in mice. Gastroenterology 2002; 122: 1913-23. Back to cited text no. 8 [PUBMED] [FULLTEXT] |
9. | Wallace JL. Nonsteroidal antiinflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997; 112: 1000-16. Back to cited text no. 9 [PUBMED] [FULLTEXT] |
10. | Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T, Stenson WF. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 1998; 115: 297-306. Back to cited text no. 10 [PUBMED] [FULLTEXT] |
11. | Hilsden RJ, Meddings JB, Sutherland LR. Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn's disease. Gastroenterology 1996;110:1395-403. Back to cited text no. 11 [PUBMED] [FULLTEXT] |
12. | Roberts PJ, Morgan K, Miller R, Hunter JO, Middleton SJ. Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease. Gut 2001;48: 468-72. Back to cited text no. 12 [PUBMED] [FULLTEXT] |
13. | Newberry RD, Stenson WF, Lorenz RG. Cyclooxygenase 2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 1999; 5: 900-6. Back to cited text no. 13 [PUBMED] [FULLTEXT] |
14. | Duchmann R, Kaiser DW, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 1995; 102: 448-55. Back to cited text no. 14 |
15. | Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433-42. Back to cited text no. 15 [PUBMED] [FULLTEXT] |
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